111

FULL PAPER

DOI: 10.1002/ejoc.200900825

A New Synthesis of Sulfur-, Nitrogen- and Oxygen-ContainingEight-Membered Ring Lactams

Rebekka Pflantz,[a] Jonas Sluiter,[a] Mario Kricka,[a] Wolfgang Saak,[a] Christoph Hoenke,[b]and Jens Christoffers*[a]

Keywords: Lactams / Heterocycles / Sulfur compounds / Medium ring compounds / Ring expansion / Amines

Bi(NO3)3-catalyzed ring expansion of five-membered ring1,4-diketones in the presence of primary amines leads toeight-membered ring lactams. When applied to starting ma-terials with a tetrahydrothiophene or pyrrolidine moiety,tetrahydro-2H-1,4-thiazocin-3-ones and hexahydro-1,4-di-azocin-2-ones are obtained as representatives of these very

Introduction

Eight-membered ring lactams 2 are new scaffolds forcombinatorial chemistry and can be prepared by bismuthnitrate catalyzed ring expansion of 1,4-diketones 1 in thepresence of primary amines RANH2 (Scheme 1).[1] Wehave recently used this transformation for the preparationof amides 4 with three points of diversification (RA, RB,and RC). Aromatic residue RB originated from the startingmaterial 1. After ring expansion, the ester moieties weresaponified and amidated with another set of primaryamines RCNH2 to give products 4.[2] A mechanistic ration-ale for the ring expanding transformation considers nucleo-philic attack of the amine to both carbonyl groups of the1,4-diketone moiety with formation of the bicyclic interme-diate 3, as proposed for the PaalKnorr pyrrole synthesis.

We considered -oxo esters with a tetrahydrothiophenering (5), pyrrolidine ring (6) or tetrahydrofuran ring (7) tobe appropriate starting materials for the synthesis of nitro-gen, sulfur or oxygen containing eight-membered ring lac-tams 8, 9 and 10 (Scheme 2). Whereas benzo- and dibenzo-annulated 1,4-diazocanes,[3] 1,4-thiazocanes[4] and 1,4-oxazocanes[5] frequently appeared in the literature, onlyvery few synthetic pathways to monocyclic 1,4-di-azocanes,[6] 1,4-thiazocanes[7] and 1,4-oxazocanes[8] havebeen reported so far. Therefore, the Bi(NO3)3-catalyzed ringexpanding reaction is interesting as it allows a straightfor-ward access to these rare eight-membered heterocycles.

[a] Institut fr Reine und Angewandte Chemie, Carl von Ossietzky-Universitt Oldenburg,26111 Oldenburg, GermanyFax: +49-441-798-3873E-mail: [email protected]

[b] Boehringer Ingelheim Pharma GmbH & Co. KG, AbteilungChemische Forschung,Birkendorfer Str. 65, 88397 Biberach an der Ri, Germany

Eur. J. Org. Chem. 2009, 54315436 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5431

rare heterocyclic systems. In the case of tetrahydrofuran de-rivatives, other reaction conditions are required and yields oftetrahydro-2H-1,4-oxazocin-3-ones are very low.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,Germany, 2009)

Scheme 1. Preparation of a model library of eight-membered ringlactams 4 from 1,4-diketones 1 and primary amines RANH2 andRCNH2.

Scheme 2. Synthetic plan for tetrahydro-2H-1,4-thiazocin-3-ones 8,hexahydro-1,4-diazocin-2-ones 9, and tetrahydro-2H-1,4-oxazocin-3-ones 10.

Results and Discussion

The hitherto unknown tetrahydrothiophene, pyrrolidineand tetrahydrofuran derivatives 5, 6 and 7 with a 1,4-dike-tone motif were accessed starting from the corresponding-oxo esters 11, 12 and 13 (Scheme 3). The pyrrolidinederivative 12 was prepared from tert-butyl bromoacetate,

J. Christoffers et al.FULL PAPERbenzylamine and methyl acrylate according to a literatureprocedure.[9] The tetrahydrothiophene and -furan deriva-tives 11 and 13 were accessed from methyl acrylate andmethyl thioglycolate[10] or methyl glycolate,[11] respectively,both as reported in the literature. Alkylations of these three-oxo esters 1113 with phenacyl bromide and K2CO3 inacetone or NaH in THF were unproblematic and proceededwith good yields.

Scheme 3. Synthesis of 1,4-diketones 57 from heterocyclic -oxoesters 1113, conditions a) for 5 and 6: 1.1 equiv. K2CO3, acetone,1 h, 65 C; b) for 7: 1.2 equiv. NaH, THF, 16 h, 70 C.

1,4-Diketones 5 and 6 were converted with an excess ofprimary amines in the presence of sub-stoichiometricamounts of Bi(NO3)35H2O. Initial optimization of thistransformation was carried out with the tetrahydrothio-phene derivative 5 and BnNH2 (Table 1, entry 1, product8a). The reaction conditions given in Scheme 4 wereadopted for all four amines RNH2 (Table 1). Reactionswere performed with THF as solvent at 100 C, thus, tightlyclosed vials were used as flasks. For larger volumes(20 mL), the reaction mixture was split up into severalvials for the reaction and recombined for workup and puri-fication. Yields of thiazocine products 8a8d are in therange of 5070%. Correlations between yields and steric orelectronic influence of the amine cannot be identified.Yields of diazocine products 9a9c (Table 1) are signifi-cantly lower. Moreover, in the case of a primary amine withsecondary alkyl residue (CyNH2) the formation of product9d failed completely.

Table 1. Amines used for the ring expansion reactions and yieldsof thiazocines 8 and diazocines 9.

Entry Amine RNH2 Yield of 8 (X = S) Yield of 9 (X = NBn)

1 PhCH2NH2 56% (8a) 35% (9a)2 MeNH2[a] 68% (8b) 20% (9b)3 AllylNH2 51% (8c) 31% (9c)4 CyNH2 62% (8d) (9d)[b]

[a] Solution (2 moldm3) in THF was used. [b] No product detect-able.

Scheme 4. Synthesis of 1,4-thiazocin-3-ones 8a8d and 1,4-di-azocin-3-ones 9a9c. For residues R and yields see Table 1.

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We planned to obtain a X-ray single-crystal structure inorder to proof the constitution of our lactams, but we failedto obtain single crystals of compounds 8 and 9. Therefore,we have prepared p-iodophenylamide 15 from N-methyl-thiazocinone 8b by ester saponification and amidation ofthe carboxylic acid 14 with DCC, HOBt (Scheme 5). Com-pound 15 with iodine as heavy atom showed good crystal-linity and suitable single crystals were obtained and investi-gated.[12] Figure 1 shows the structure in the solid state. Theeight-membered ring is in a folded, crown-shaped confor-mation. The enamine CC double bond and the amide NCO plane are almost perpendicular (dihedral angle C5C6N1C7: 114.18).

Scheme 5. Ester saponification and amidation.

Figure 1. ORTEP-representation of the structure of amide 15 in thesolid state.

We of course tried to convert tetrahydrofuran derivative7 with primary amines and catalytic amounts of Bi salt inorder to access tetrahydrooxazocines, but even under dif-ferent reaction conditions, we were never able to detecteight-membered ring products like 10. Therefore, we at-tempted other Lewis acids [Sc(OTf)3, FeCl36H2O,CeCl37H2O, ZnCl2] as well as Brnsted acids (H2SO4, HCl/H2O, KHSO4, AcOH) as catalysts, but remained unsuccess-ful. To our surprise and after extensive experimentation, wewere able to obtain compound 10 in low yield together withbyproduct 16 when using 2 equiv. of MeNH2 and 1 equiv.pTosOH as an additive, if all starting materials are mixedat 0 C (Scheme 6). The open-chain product 16 is clearlyresulting from retro-Dieckmann reaction of intermediate

New Synthesis of S-, N- and O-Containing Lactams

hemi-aminal anion 17 after addition of the amine to thecarbonyl group C-4. Compared with the sulfur and nitrogencogeners 5 and 6, the addition of MeNH2 to the more elec-trophilic carbonyl group C-4 of compound 7 might be fa-voured by the I-effect of the ether oxygen. Even after ex-tensive variation of stoichiometry and other reaction condi-tions, we were not able to raise the amount of formed eight-membered ring product 10 and minimize the formation ofamide 16 in the reaction mixtures. Even worse, we com-pletely failed to obtain any product of type 10 when usingother amines than MeNH2. Finally, we conclude that ringexpansion of diketone 7 is not a suitable method for thepreparation of oxazocines like compound 10 on a prepara-tive useful scale. Nevertheless, we were able to grow singlecrystals of compound 10 and obtained a X-ray structure,which is shown in Figure 2. It shows the same key featureslike compound 15: crown-shaped conformation of theeight-membered ring and almost perpendicular CC-doublebond and amide moiety (dihedral angle C5C6N1C7:118.96).

Scheme 6. Attempts on preparation of oxazocine 10.

Figure 2. ORTEP representation of the structure of lactam 10 inthe solid state.

Experimental SectionGeneral Methods: Preparative column chromatography was carriedout using Merck SiO2 (0.0350.070 mm, type 60 A) with hexaneand ethyl acetate (EA) or tert-butyl methyl ether (MTBE) as el-uents. TLC was performed on Merck SiO2 F254 plates on alumin-ium sheets. 1H- and 13C-NMR spectra were recorded on a BrukerAvance DRX 500 and Avance DPX 300. Multiplicities were deter-mined with DEPT experiments. EI-MS, CI-MS and HRMS spectra

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were obtained with a Finnigan MAT 95 spectrometer, ESI-MS(HRMS) spectra with a Waters Q-TOF Premier. IR spectra wererecorded on a Bruker Tensor 27 spectrometer equipped with aGoldenGate diamond-ATR unit. Elemental analyses weremeasured with a Euro EA-CHNS from HEKAtech. Oxo esters11,[10] 12[9] and 13[11] were prepared according to literature proto-cols. All other starting materials were commercially available.MeNH2 in THF was obtained from Aldrich.

Methyl 4-Oxo-3-(2-oxo-2-phenylethyl)tetrahydrothiophene-3-carb-oxylate (5): K2CO3 (7.10 g, 72.1 mmol, 1.1 equiv.) and phenacylbromide (15.7 g, 78.7 mmol, 1.2 equiv.) were added successively toa solution of compound 11 (10.5 g, 65.5 mmol, 1.0 equiv.) in ace-tone (65 mL). The resulting mixture was stirred for 1 h at 65 C,then cooled to ambient temperature and diluted with H2O (65 mL).The layers were separated and the aqueous layer extracted withMTBE (365 mL). The combined organic layers were dried(MgSO4), filtered and the solvent evaporated to give compound5 (16.8 g, 60.3 mmol, 92%) after chromatography (SiO2, hexane/MTBE, 2:1, Rf = 0.20) as a yellow oil. 1H NMR (CDCl3,500 MHz): = 3.30 (A-part of an AB-system, J = 12.1 Hz, 1 H),3.48 (A-part of an AB-system, J = 17.3 Hz, 1 H), 3.58 (B-part ofan AB-system, J = 17.3 Hz, 1 H), 3.63 (B-part of an AB-system, J= 11.9 Hz, 1 H), 3.64 (A-part of an AB-system, J = 18.6 Hz, 1 H),3.75 (s, 3 H), 3.78 (B-part of an AB-system, J = 18.3 Hz, 1 H),7.447.47 (m, 2 H), 7.567.59 (m, 1 H), 7.917.92 (m, 2 H) ppm.13C{1H} NMR (CDCl3, 125 MHz): = 34.79 (CH2), 37.79 (CH2),42.66 (CH2), 53.27 (CH3), 58.48 (C), 128.06 (2 CH), 128.70 (2 CH),133.74 (CH), 135.89 (C), 169.85 (C), 195.84 (C), 207.52 (C) ppm.IR (ATR): = 2953 (w), 1727 (vs), 1682 (vs), 1596 (m), 1448 (s),1398 (m), 1351 (m), 1285 (m), 1218 (vs), 1098 (m), 1046 (m), 1000(m), 775 (s), 688 (vs) cm1. MS (EI, 70 eV): m/z (%) = 278 (9) [M+],173 (17), 159 (46), 120 (34), 105 (100). HRMS (EI, 70 eV): calcd.278.0613 (for C14H14O4S); found 278.0611 [M+]. C14H14O4S(278.32).

Methyl 1-Benzyl-4-oxo-3-(2-oxo-2-phenylethyl)pyrrolidine-3-carb-oxylate (6): K2CO3 (3.47 g, 25.1 mmol, 1.05 equiv.) and phenacylbromide (5.00 g, 25.1 mmol, 1.05 equiv.) were added successively toa solution of compound 12 (5.57 g, 23.9 mmol, 1.0 equiv.) in ace-tone (30 mL). The resulting mixture was stirred for 2 h at 65 C,then cooled to ambient temperature and diluted with H2O (30 mL).The layers were separated and the aqueous layer extracted withMTBE (330 mL). The combined organic layers were dried(MgSO4), filtered and the solvent evaporated to give compound 6(7.91 g, 22.5 mmol, 94%) as a yellow brown oil, which could beused without further purification. 1H NMR (CDCl3, 500 MHz): = 3.11 (d, J = 10.0 Hz, 1 H), 3.18 (A-part of an AB-system, J =17.1 Hz, 1 H), 3.26 (B-part of an AB-system, J = 17.1 Hz, 1 H),3.49 (d, J = 18.1 Hz, 1 H), 3.67 (d, J = 10.0 Hz, 1 H), 3.69 (A-partof an AB-system, J = 13.1 Hz, 1 H), 3.72 (s, 3 H), 3.79 (d, J =18.2 Hz, 1 H), 3.82 (B-part of an AB-system, J = 13.2 Hz, 1 H),7.287.30 (m, 5 H), 7.417.46 (m, 2 H), 7.537.57 (m, 1 H), 7.907.93 (m, 2 H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): = 41.50(CH2), 52.78 (CH3), 58.68 (C), 59.04 (CH2), 59.70 (CH2), 60.47(CH2), 127.25 (CH), 127.94 (2 CH), 128.30 (2 CH), 128.43 (2 CH),128.56 (2 CH), 133.45 (CH), 136.03 (C), 137.23 (C), 169.28 (C),196.01 (C), 208.57 (C) ppm. IR (ATR): = 3063 (w), 2952 (w),1766 (m), 1728 (vs), 1682 (vs), 1597 (m), 1449 (m), 1434 (m), 1354(m), 1215 (vs), 1177 (s), 1076 (s), 1044 (m), 1028 (m), 1001 (m),754 (s), 689 (vs) cm1. MS (EI, 70 eV): m/z (%) = 351 (13) [M+],292 (18), 232 (36), 200 (48), 105 (16), 91 (100). HRMS (EI, 70 eV):calcd. 351.1471 (for C21H21NO4); found 351.1468 [M+].C21H21NO4 (351.40).

J. Christoffers et al.FULL PAPERMethyl 4-Oxo-3-(2-oxo-2-phenylethyl)tetrahydrofuran-3-carboxyl-ate (7): NaH (60% dispersion in mineral oil, 1.36 g, 34.0 mmol)and phenacyl bromide (6.8 g, 34 mmol) were added to a solutionof compound 13 (4.0 g, 28 mmol) in THF (30 mL) and the mixturewas stirred for 16 h at 70 C. After cooling to ambient temperature,it was diluted with H2O (30 mL) and washed with brine (30 mL).The layers were separated and the aqueous layer extracted withMTBE (330 mL). The combined organic layers were dried(MgSO4), filtered and the solvent evaporated. The residue waschromatographed (SiO2, hexane/MTBE, 1:1, Rf = 0.21) to givecompound 7 (4.56 g, 17.4 mmol, 62%) as a light pink oil. 1H NMR(CDCl3, 500 MHz): = 3.42 (A-part of an AB-system, J = 18.5 Hz,1 H), 3.70 (s, 3 H), 3.83 (B-part of an AB-system, J = 18.4 Hz, 1H), 4.13 (A-part of an AB-system, J = 16.9 Hz, 1 H), 4.17 (A-partof an AB-system, J = 9.9 Hz, 1 H), 4.19 (B-part of an AB-system,J = 16.9 Hz, 1 H), 4.79 (B-part of an AB-system, J = 9.9 Hz, 1 H),7.397.42 (m, 2 H), 7.517.54 (m, 1 H), 7.877.88 (m, 2 H) ppm.13C{1H} NMR (CDCl3, 125 MHz): = 41.17 (CH2), 53.29 (CH3),56.73 (C), 70.70 (CH2), 74.63 (CH2), 128.14 (2 CH), 128.77 (2 CH),133.87 (CH), 135.71 (C), 168.82 (C), 195.90 (C), 209.85 (C) ppm.IR (ATR): = 2954 (w), 1729 (vs), 1683 (s), 1597 (m), 1449 (m),1355 (m), 1220 (vs), 1001 (m), 756 (vs), 689 (s) cm1. MS (EI,70 eV): m/z (%) = 262 (3) [M+], 232 (10), 143 (25), 120 (22), 105(100). HRMS (EI, 70 eV): calcd. 262.0841 (for C14H14O5); found262.0836 [M+]. C14H14O5 (262.26).

General Procedure A. Bismuth-Catalyzed Preparation of Lactams:The respective amine RNH2 (23 equiv.) was added to a mixtureof Bi(NO3)35H2O (0.1 equiv.) and compound 5 or 6 (1.0 equiv.) inTHF (c = 0.7 moldm3). The resulting mixture was stirred for 46 hat 100 C in a tightly closed reaction vial. After cooling to ambienttemperature, the reaction mixture was diluted with EA (ca. 510 dm3 mol1) and extracted with H2O (ca. 510 dm3 mol1). Afterphase separation, the aqueous layer was again extracted with EA(2510 dm3 mol1). The combined organic layers were dried(MgSO4), filtered and the solvent evaporated to give products 8 or9 as crude materials, which were purified by chromatography onSiO2.

Methyl 4-Benzyl-3-oxo-5-phenyl-3,4,7,8-tetrahydro-2H-1,4-thiazoc-in-7-carboxylate (8a): According to general procedure A, reactionof benzylamine (3.86 g, 36.0 mmol), compound 5 (5.0 g, 18 mmol)and Bi(NO3)35H2O (870 mg, 1.80 mmol) gave product 8a (3.71 g,10.1 mmol, 56%) after chromatography (SiO2, hexane/EA, 2:1, Rf= 0.23) as a yellow oil. 1H NMR (CDCl3, 500 MHz): = 2.53 (dd,J = 10.0, J = 13.8 Hz, 1 H), 2.72 (t, J = 9.9 Hz, 1 H), 2.84 (d, J =13.9 Hz, 1 H), 3.23 (A-part of an AB-system, J = 13.6 Hz, 1 H),3.50 (B-part of an AB-system, J = 13.6 Hz, 1 H), 3.56 (s, 3 H),3.62 (A-part of an AB-system, J = 13.7 Hz, 1 H), 5.57 (B-part ofan AB-system, J = 13.7 Hz, 1 H), 5.88 (d, J = 9.9 Hz, 1 H), 7.297.36 (m, 5 H), 7.427.44 (m, 5 H) ppm. 13C{1H} NMR (CDCl3,125 MHz): = 30.97 (CH2), 31.71 (CH2), 47.15 (CH), 48.27 (CH2),52.11 (CH3), 124.46 (CH), 126.34 (2 CH), 127.58 (CH), 128.42 (2CH), 129.19 (2 CH), 129.56 (CH), 129.66 (2 CH), 135.13 (C),135.78 (C), 140.22 (C), 169.76 (C), 172.19 (C) ppm. IR (ATR): = 3028 (w), 2948 (w), 1731 (s), 1650 (vs), 1493 (m), 1433 (m), 1391(m), 1317 (m), 1244 (m), 1167 (s), 1076 (m), 1028 (m), 913 (m), 867(m), 761 (s), 730 (s), 696 (vs) cm1. MS (EI, 70 eV): m/z (%) = 367(9) [M+], 234 (42), 220 (12), 91 (100). C21H21NO3S (367.46): calcd.C 68.64, H 5.76, N 3.81; found C 68.74, H 5.91, N 4.20. HRMS(EI, 70 eV): calcd. 367.1242; found 367.1243 [M+].

Methyl 4-Methyl-3-oxo-5-phenyl-3,4,7,8-tetrahydro-2H-1,4-thiazoc-in-7-carboxylate (8b): According to general procedure A, reactionof methylamine (14.4 mmol, 7.20 mL of a 2.00 moldm3 solution in


THF), compound 5 (2.0 g, 7.2 mmol) and Bi(NO3)35H2O (340 mg,0.720 mmol) gave product 8b (1.43 g, 4.90 mmol, 68%) afterchromatography (SiO2, hexane/EA, 2:1, Rf = 0.16) as a yellow oil.1H NMR (CDCl3, 500 MHz): = 2.53 (dd, J = 9.8, J = 13.9 Hz,1 H), 2.81 (s, 3 H), 2.88 (d, J = 13.9 Hz, 1 H), 3.00 (A-part of anAB-system, J = 13.6 Hz, 1 H), 3.27 (d, J = 9.8 Hz, 1 H), 3.31 (B-part of an AB-system, J = 13.5 Hz, 1 H), 3.62 (s, 3 H), 5.79 (d, J= 10.0 Hz, 1 H), 7.217.23 (m, 5 H) ppm. 13C{1H} NMR (CDCl3,125 MHz): = 30.94 (CH2), 31.16 (CH2), 33.68 (CH3), 47.33 (CH),52.47 (CH3), 121.82 (CH), 125.99 (2 CH), 128.93 (2 CH), 129.38(CH), 134.71 (C), 142.50 (C), 170.27 (C), 172.34 (C) ppm. IR(ATR): = 3082 (w), 2950 (m), 1732 (s), 1647 (vs), 1426 (m), 1375(s), 1324 (m), 1246 (m), 1160 (s), 1065 (w), 866 (m), 766 (s), 696 (s)cm1. MS (EI, 70 eV): m/z (%) = 291 (30) [M+], 234 (100), 205 (24),186 (50), 158 (40), 133 (39), 118 (81), 91 (23). HRMS (EI, 70 eV):calcd. 291.0929 (for C15H17NO3S); found 291.0927 [M+].C15H17NO3S (291.37).

Methyl 4-Allyl-3-oxo-5-phenyl-3,4,7,8-tetrahydro-2H-1,4-thiazocin-7-carboxylate (8c): According to general procedure A, reaction ofallylamine (205 mg, 3.40 mmol), compound 5 (500 mg, 1.70 mmol)and Bi(NO3)35H2O (88 mg, 0.19 mmol) gave product 8c (290 mg,0.913 mmol, 51%) after chromatography (SiO2, hexane/EA, 2:1, Rf= 0.27) as a yellow oil. 1H NMR (CDCl3, 500 MHz): = 2.69 (dd,J = 9.9, J = 14.0 Hz, 1 H), 3.02 (d, J = 13.9 Hz, 1 H), 3.20 (A-partof an AB-system, J = 13.6 Hz, 1 H), 3.24 (dd, J = 14.2, J = 8.1 Hz,1 H), 3.45 (t, J = 10.0 Hz, 1 H), 3.48 (B-part of an AB-system, J= 13.6 Hz, 1 H), 3.78 (s, 3 H), 4.81 (dd, J = 14.2, J = 5.8 Hz, 1 H),5.04 (d, J = 17.0 Hz, 1 H), 5.11 (d, J = 10.0 Hz, 1 H), 5.80 (dddd,J = 17.0, J = 10.0, J = 8.1, J = 5.8 Hz, 1 H), 5.99 (d, J = 9.9 Hz,1 H), 7.367.38 (m, 2 H), 7.407.41 (m, 3 H) ppm. 13C{1H} NMR(CDCl3, 125 MHz): = 31.16 (CH2), 31.54 (CH2), 47.65 (CH2),47.93 (CH), 52.58 (CH3), 119.75 (CH2), 123.65 (CH), 126.18 (2CH), 129.00 (2 CH), 129.47 (CH), 131.18 (CH), 135.05 (C), 140.83(C), 169.81 (C), 172.58 (C) ppm. IR (ATR): = 2951 (w), 1732(vs), 1650 (s), 1390 (m), 1316 (m), 1249 (m), 1154 (s), 1115 (m),924 (m), 866 (m), 766 (s), 696 (vs) cm1. MS (EI, 70 eV): m/z (%)= 317 (22) [M+], 270 (16), 258 (34), 231 (38), 212 (31), 191 (50),170 (38), 144 (52), 115 (34), 41 (100). C17H19NO3S (317.40): calcd.C 64.33, H 6.03, N 4.41; found C 64.29, H 6.29, N 4.79. HRMS(EI, 70 eV): calcd. 317.1086 (for C17H19NO3S); found 317.1088[M+].

Methyl 4-Cyclohexyl-3-oxo-5-phenyl-3,4,7,8-tetrahydro-2H-1,4-thiazocin-7-carboxylate (8d): According to general procedure A, re-action of cyclohexylamine (4.27 g, 14.4 mmol), compound 5(6.00 g, 21.6 mmol) and Bi(NO3)35H2O (1.05 g, 2.16 mmol) gaveproduct 8d (4.82 g, 13.4 mmol, 62%) after chromatography (SiO2,hexane/EA, 2:1, Rf = 0.28) as a yellow oil. 1H NMR (CDCl3,500 MHz): = 0.88 (tq, J = 3.6, J = 13.1 Hz, 1 H), 0.95 (dq, J =3.6, J = 12.4 Hz, 1 H), 1.171.31 (m, 2 H), 1.37 (dq, J = 3.4, J =12.4 Hz, 1 H), 1.51 (d, J = 13.0 Hz, 1 H), 1.57 (dd, J = 2.4, J =13.4 Hz, 1 H), 1.70 (dt, J = 2.3, J = 11.8 Hz, 2 H), 1.72 (d, J =11.8 Hz, 1 H), 2.68 (dd, J = 9.9, J = 14.0 Hz, 1 H), 3.00 (d, J =13.9 Hz, 1 H), 3.16 (A-part of an AB-system, J = 13.9 Hz, 1 H),3.51 (B-part of an AB-system, J = 13.5 Hz, 1 H), 3.54 (t, J =9.6 Hz, 1 H), 3.80 (s, 3 H), 4.12 (tt, J = 3.5, J = 12.1 Hz, 1 H),5.91 (d, J = 10.1 Hz, 1 H), 7.367.39 (m, 5 H) ppm. 13C{1H} NMR(CDCl3, 125 MHz): = 25.17 (CH2), 25.82 (2 CH2), 30.12 (CH2),30.78 (CH2), 31.51 (CH2), 32.16 (CH2), 47.61 (CH), 52.60 (CH3),56.05 (CH), 126.04 (CH), 126.16 (2 CH), 128.54 (2 CH), 129.11(CH), 137.94 (C), 140.57 (C), 169.68 (C), 172.39 (C) ppm. IR(ATR): = 2933 (m), 2856 (m), 1735 (vs), 1639 (vs), 1447 (m), 1357(m), 1248 (m), 1165 (s), 766 (s), 645 (s) cm1. MS (EI, 70 eV): m/z(%) = 359 (36) [M+], 300 (25), 277 (45), 234 (100), 228 (33), 191

New Synthesis of S-, N- and O-Containing Lactams

(26), 172 (59), 156 (27), 120 (16), 104 (17). HRMS (EI, 70 eV):calcd. 359.1555 (for C20H25NO3S); found 359.1553 [M+].C20H25NO3S (359.48).

Methyl 1,4-Dibenzyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahydro-1,4-di-azocin-6-carboxlate (9a): According to general procedure A, reac-tion of benzylamine (0.90 g, 8.4 mmol), compound 6 (1.00 g,2.85 mmol) and Bi(NO3)35H2O (136 mg, 0.280 mmol) gave com-pound 9a (432 mg, 0.981 mmol, 35%) after chromatography (SiO2,hexane/EA, 2:1, Rf = 0.50) as a yellow oil. 1H NMR (CDCl3,500 MHz): = 2.34 (dd, J = 13.2, J = 8.9 Hz, 1 H), 2.50 (t, J =9.1 Hz, 1 H), 3.01 (d, J = 13.3 Hz, 1 H), 3.41 (d, J = 13.0 Hz, 1H), 3.45 (d, J = 13.6 Hz, 1 H), 3.47 (s, 3 H), 3.60 (d, J = 12.9 Hz,1 H), 3.59 (d, J = 13.7 Hz, 1 H), 4.09 (d, J = 13.9 Hz, 1 H), 5.47(d, J = 13.7 Hz, 1 H), 5.93 (d, J = 9.3 Hz, 1 H), 7.207.35 (m, 15H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): = 41.64 (CH), 48.05(CH2), 51.87 (CH3), 53.44 (CH2), 55.50 (CH2), 57.42 (CH2), 124.62(CH), 126.39 (2 CH), 127.32 (CH), 127.54 (CH), 128.24 (4 CH),128.98 (2 CH), 129.14 (CH), 129.27 (4 CH), 135.30 (C), 136.04 (2C), 139.43 (C), 167.78 (C), 172.40 (C) ppm. IR (ATR): = 3060(w), 2950 (w), 1733 (s), 1644 (s), 1494 (m), 1447 (m), 1435 (m),1397 (m), 1304 (m), 1254 (m), 1223 (m), 1198 (m), 1170 (m), 1114(m), 1075 (m), 1028 (m), 913 (m), 767 (m), 755 (m), 732 (s), 697(vs) cm1. HRMS (ESI): calcd. 441.2178 (for C28H29N2O3); found441.2187 [M + H+]. C28H28N2O3 (440.53).

Methyl 4-Benzyl-1-methyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahydro-1,4-diazocin-6-carboxylate (9b): According to general procedure A,reaction of methylamine (8.4 mmol, 4.2 mL of a 2.00 moldm3

solution in THF), compound 6 (1.00 g, 2.85 mmol) and Bi(NO3)35H2O (136 mg, 0.280 mmol) gave compound 9b (204 mg,0.560 mmol, 20 %) after chromatography (SiO2, hexane/EA, 2:1, Rf= 0.40) as a yellow oil. 1H NMR (CDCl3, 500 MHz): = 2.47 (dd,J = 13.6, J = 8.8 Hz, 1 H), 2.88 (s, 3 H), 3.173.21 (m, 2 H), 3.41(A-part of an AB-system, J = 13.2 Hz, 1 H), 3.56 (B-part of anAB-system, J = 13.2 Hz, 1 H), 3.58 (d, J = 13.9 Hz, 1 H), 3.64 (s,3 H), 4.10 (d, J = 13.9 Hz, 1 H), 5.98 (d, J = 9.3 Hz, 1 H), 7.167.33 (m, 10 H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): = 33.61(CH3), 42.08 (CH), 52.20 (CH3), 54.32 (CH2), 55.32 (CH2), 57.36(CH2), 122.05 (CH), 126.19 (2 CH), 127.14 (CH), 128.18 (2 CH),128.84 (2 CH), 129.03 (CH), 129.07 (2 CH), 135.27 (C), 138.28 (C),141.60 (C), 168.88 (C), 173.00 (C) ppm. IR (ATR): = 3061 (w),2953 (w), 1734 (s), 1647 (s), 1449 (m), 1436 (m), 1386 (m), 1347(m), 1312 (m), 1252 (m), 1204 (m), 1168 (m), 1072 (m), 1030 (m),859 (m), 769 (s), 740 (m), 699 (vs) cm1. MS (EI, 70 eV): m/z (%)= 364 (27) [M+], 307 (60), 278 (35), 244 (10), 216 (17), 204 (49),158 (26), 144 (19), 118 (27), 91 (100). HRMS (EI, 70 eV): calcd.364.1787 (for C22H24N2O3); found 364.1791 [M+]. C22H24N2O3(364.44).

Methyl 1-Allyl-4-benzyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahydro-1,4-diazocin-6-carboxylate (9c): According to general procedure A, re-action of allylamine (479 mg, 8.40 mmol), compound 6 (1.00 g,2.85 mmol) and Bi(NO3)35H2O (136 mg, 0.280 mmol) gave com-pound 9c (339 mg, 0.868 mmol, 31%) after chromatography (SiO2,hexane/EA, 2:1, Rf = 0.43) as a yellow oil. 1H NMR (CDCl3,500 MHz): = 2.56 (dd, J = 13.4, J = 8.8 Hz, 1 H), 3.223.34 (m,3 H), 3.50 (A-part of an AB-system, J = 13.2 Hz, 1 H), 3.66 (d, J= 13.9 Hz, 1 H), 3.67 (B-part of an AB-system, J = 13.0 Hz, 1 H),3.74 (s, 3 H), 4.21 (d, J = 14.0 Hz, 1 H), 4.78 (dd, J = 14.3, J =5.6 Hz, 1 H), 5.05 (d, J = 17.1 Hz, 1 H), 5.14 (d, J = 10.0 Hz, 1H), 5.81 (dddd, J = 17.1, J = 10.0, J = 7.9, J = 5.8 Hz, 1 H), 6.13(d, J = 9.4 Hz, 1 H), 7.307.45 (m, 10 H) ppm. 13C{1H} NMR(CDCl3, 125 MHz): = 41.94 (CH), 47.48 (CH2), 52.29 (CH3),53.92 (CH2), 55.34 (CH2), 57.53 (CH2), 199.43 (CH2), 123.68 (CH),

Eur. J. Org. Chem. 2009, 54315436 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 5435

126.37 (3 CH), 127.48 (CH), 128.21 (2 CH), 128.85 (3 CH), 129.14(CH), 129.35 (CH), 131.38 (C), 137.28 (C), 140.15 (C), 167.57 (C),172.60 (C) ppm. IR (ATR): = 3060 (w), 2950 (w), 1733 (s), 1644(s), 1447 (m), 1435 (m), 1396 (m), 1335 (m), 1306 (m), 1254 (m),1197 (m), 1166 (s), 1134 (m), 1097 (m), 1076 (m), 1028 (m), 1000(m), 926 (m), 767 (s), 741 (m), 696 (s) cm1. MS (EI, 70 eV): m/z(%) = 390 (28) [M+], 307 (19), 230 (17), 202 (76), 170 (13), 134 (16),91 (100). HRMS (EI, 70 eV): calcd. 390.1943 (for C24H26N2O3);found 390.1947 [M+]. C24H26N2O3 (390.48).

4-Methyl-3-oxo-5-phenyl-3,4,7,8-tetrahydro-2H-1,4-thiazocin-7-carboxylic Acid (14): A solution of LiOH in H2O (c = 2 moldm3,16.8 mmol, 8.40 mL) was added to compound 8b (490 mg,1.68 mmol) in EtOH (8.5 mL) and the resulting mixture was stirredfor 2 h at 70 C. After cooling to ambient temperature, it was di-luted with H2O (12 mL) and washed with CH2Cl2 (30 mL). Theaqueous layer was acidified with concentrated hydrochloric acid(ca. 5 mL) and extracted with MTBE (330 mL). The combinedorganic extracts were dried (MgSO4), filtered and the solvent evap-orated to give compound 14 (390 mg, 1.41 mmol, 84%) as an ana-lytically pure product without purification and as beige solid, mp.148 C. 1H NMR (CDCl3, 500 MHz): = 2.73 (dd, J = 9.7, J =14.0 Hz, 1 H), 3.04 (s, 3 H), 3.15 (A-part of an AB-system, J =13.9 Hz, 1 H), 3.32 (B-part of an AB-system, J = 13.8 Hz, 1 H),3.51 (t, J = 9.6 Hz, 2 H), 6.04 (d, J = 9.9 Hz, 1 H), 7.387.44 (m,5 H), 11.31 (br. s, 1 H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): = 30.93 (CH2), 31.20 (CH2), 34.15 (CH3), 47.40 (CH), 122.14 (CH),126.10 (2 CH), 129.10 (2 CH), 129.65 (CH), 134.40 (C), 142.39 (C),171.32 (C), 175.75 (C) ppm. IR (ATR): = 2969 (w), 2925 (w),1737 (s), 1712 (vs), 1608 (s), 1433 (m), 1380 (s), 1317 (m), 1192 (s),1109 (w), 881 (m), 767 (s), 697 (s) cm1. MS (EI, 70 eV): m/z (%)= 277 (19) [M+], 230 (16), 220 (51), 186 (23), 158 (14), 118 (33), 89(51), 45 (100). C14H15NO3S (277.34): calcd. C 60.63, H 5.45, N5.05; found C 60.82, H 5.11, N 5.18. HRMS (EI, 70 eV): calcd.277.0773 (for C14H15NO3S); found 277.0776 [M+].

4-Methyl-3-oxo-5-phenyl-3,4,7,8-tetrahydro-2H-1,4-thiazocin-7-carboxylic Acid (4-Iodophenyl)amide (15): DCC (123 mg, 0.595mmol) was added to a cooled (ice-water bath) solution of com-pound 14 (150 mg, 0.541 mmol) in CH2Cl2 (3 mL). After stirringthe mixture for 1 min, HOBt (100 mg, 0.649 mmol) was added, andthe mixture was stirred further for 1 min at 23 C. 4-Iodoaniline(237 mg, 1.08 mmol) was then added and the mixture stirred for16 h at 50 C. After cooling to ambient temperature, the mixturewas diluted with CH2Cl2 (20 mL) and washed with sat. NH4Clsolution (20 mL), sat. NaHCO3 solution (20 mL) and H2O(20 mL). The organic layer was dried (MgSO4), filtered, and thesolvent evaporated. The residue was chromatographed (SiO2, hex-ane/EA, 2:1, Rf = 0.21) to give compound 15 (180 mg, 0.379 mmol,70%) as a yellow solid, mp. 106 C. Single crystals were obtainedby slow diffusion of hexane into a CH2Cl2 solution. 1H NMR(CDCl3, 500 MHz): = 2.91 (dd, J = 9.6, J = 13.8 Hz, 1 H), 3.01(d, J = 13.9 Hz, 1 H), 3.06 (A-part of an AB-system, J = 13.6 Hz,1 H), 3.15 (s, 3 H), 3.56 (t, J = 9.6 Hz, 1 H), 3.63 (B-part of anAB-system, J = 13.7 Hz, 1 H), 6.26 (d, J = 9.8 Hz, 1 H), 7.407.42(m, 5 H), 7.537.56 (m, 2 H), 7.637.66 (m, 2 H), 10.24 (br. s, 1 H)ppm. 13C{1H} NMR (CDCl3, 125 MHz): = 31.16 (CH2), 32.19(CH2), 34.23 (CH3), 49.12 (CH2), 87.20 (C), 121.61 (2 CH), 124.40(CH), 126.06 (2 CH), 129.10 (2 CH), 129.57 (CH), 134.33 (C),137.85 (2 CH), 138.65 (C), 141.27 (C), 170.82 (C), 171.54 (C) ppm.IR (ATR): = 3258 (w), 3104 (w), 2927 (w), 1687 (s), 1631 (vs),1532 (s), 1483 (s), 1389 (s), 1303 (m), 1241 (m), 1157 (m), 1061 (m),1002 (s), 821 (vs), 762 (vs), 691 (s) cm1. MS (EI, 70 eV): m/z (%)= 478 (45) [M+], 421 (100), 374 (32), 260 (21), 232 (92), 186 (50),

J. Christoffers et al.FULL PAPER158 (36), 118 (35), 91 (17). C20H19IN2O2S (478.35): calcd. C 50.22,H 4.00, N 5.86; found C 49.83, H 4.27, N 5.41.

Methyl 4-Methyl-3-oxo-5-phenyl-3,4,7,8-tetrahydro-2H-1,4-oxazoc-ine-7-carboxylate (10): Methylamine (c = 2 moldm3 solution inTHF, 0.5 mL, 1 mmol) was added to a cooled (ice-water bath) solu-tion of compound 7 (135 mg, 0.516 mmol) and pTosOH (89 mg,0.52 mmol) in THF (1 mL) and the mixture stirred in a tightlyclosed reaction vial for 1 h at 0 C and then 16 h at 80 C. Aftercooling to ambient temperature, the solvent was evaporated andthe residue chromatographed (SiO2, hexane/EA, 1:1). In a first frac-tion (Rf = 0.28) compound 10 was isolated (45 mg, 0.16 mmol,32%) as a colorless solid, mp. 115 C. In a second fraction (Rf =0.03) byproduct 16 was isolated (17 mg, 0.058 mmol, 11%) as apale yellow oil. Single crystals of product 10 were obtained by slowdiffusion of hexane into a CH2Cl2 solution. 1H NMR (CDCl3,500 MHz): = 2.91 (s, 3 H), 3.293.38 (m, 2 H), 3.71 (s, 3 H), 4.05(d, J = 12.5 Hz, 1 H), 4.19 (d, J = 8.8 Hz, 1 H), 4.23 (d, J =12.5 Hz, 1 H), 5.95 (d, J = 8.9 Hz, 1 H), 7.277.39 (m, 5 H) ppm.13C{1H} NMR (CDCl3, 125 MHz): = 34.11 (CH3), 46.35 (CH),52.52 (CH3), 69.57 (CH2), 69.66 (CH2), 120.16 (CH), 126.39(2 CH), 128.96 (2 CH), 129.35 (CH), 135.13 (C), 142.97 (C), 169.22(C), 171.59 (C) ppm. IR (ATR): = 2952 (m), 1732 (vs), 1653 (vs),1446 (s), 1388 (s), 1303 (m), 1196 (m), 1091 (s), 921 (s), 856 (m),786 (vs), 699 (vs) cm1. MS (EI, 70 eV): m/z (%) = 275 (7) [M+],218 (100), 186 (36), 158 (22), 118 (46). HRMS (ESI): calcd.298.1055 (for C15H17NNaO4); found 298.1059 [M + Na+].C15H17NO4 (275.30).

2-[2-(Methoxycarbonyl)-4-oxo-4-phenylbutoxy]-N-methylacetamide(16): Compound 16 (17 mg, 0.058 mmol, 11%) was isolated as abyproduct during the synthesis of compound 10 (chromatographyon SiO2, hexane/EA, 1:1, Rf = 0.03). 1H NMR (CDCl3, 500 MHz): = 2.85 (d, J = 5.0 Hz, 3 H), 3.25 (dd, J = 17.7, J = 6.2 Hz, 1 H),3.42 (pent, J = 5.8 Hz, 1 H), 3.55 (dd, J = 17.7, J = 6.7 Hz, 1 H),3.74 (s, 3 H), 3.753.83 (m, 2 H), 3.94 (A-part of an AB system, J= 15.4 Hz, 1 H), 3.96 (B-part of an AB system, J = 15.3 Hz, 1 H),6.82 (br. s, 1 H; NH), 7.467.53 (m, 2 H), 7.567.63 (m, 1 H), 7.948.03 (m, 2 H) ppm. 13C{1H} NMR (CDCl3, 125 MHz): = 25.48(CH3), 37.03 (CH2), 40.77 (CH), 52.22 (CH3), 70.42 (CH2), 71.41(CH2), 127.98 (2 CH), 128.63 (2 CH), 133.45 (CH), 136.21 (C),169.82 (C), 173.62 (C), 197.29 (C) ppm. IR (ATR): = 3350 (m),2953 (m), 1733 (s), 1673 (vs), 1543 (s), 1450 (m), 1223 (s), 1170 (s),1111 (vs), 1004 (m), 758 (s), 692 (s) cm1. MS (EI, 70 eV): m/z (%)= 294 (4) [M+], 221 (27), 191 (21), 174 (39), 142 (34), 120 (25), 105(100). HRMS (ESI): calcd. 316.1161 (for C15H19NNaO5); found316.1153 [M + Na+]. C15H19NO5 (293.32).

Acknowledgments

We are grateful to Dr. Michael Rssle for initial experiments,Steffen Litschel, Marvin Schulz and Matti Reissmann for assis-tance in the laboratory and to Dr. Herbert Frey for helping us withthe preparation of this manuscript.

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[12] CCDC-739826 (for 15) and -741031 (for 10) contain the sup-plementary crystallographic data for this paper. These data canbe obtained free of charge from The Cambridge Crystallo-graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Received: July 23, 2009Published Online: September 21, 2009

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